JP7042514B2 - Polymer device and fabrication method - Google Patents

Description

No description of federal-funded R & D

References to Related Applications This application claims the benefits of US Provisional Patent Application No. 62 / 371,706 filed on August 5, 2016. The disclosure of the prior application is recognized as part of the disclosure of the present application (and incorporated by reference into the disclosure of the present application).

background
LH Sperling, "Interpenetrating Polymer Networks", (in Klempner et al., Advances in Chemistry ; American Chemical Society: Washington, DC, 1994)) (Non-Patent Document 1) is a combination of two or more polymers synthesized in parallel. The interpenetrating polymer network as is being characterized.

US2003 / 0218130 (Patent Document 1) (Boschetti et al.) Refers to a substrate in which a polymerized polysaccharide-based hydrogel is bonded to the surface.

US2004 / 0162545 (Patent Document 2) (Brown et al.) Refers to the control of aqueous flow to regulate intraocular pressure in the eye.

Kim et al., ("In Situ Photopolymerization of a Polymerizable Poly (ethylene glycol)-Covered Phospholipid Monolayer on a Methacryloyl-Terminated Substrate", 402-751, Korea Langmuir, 2004, 20 (13), pp 5396-5402 DOI: 10.1021 / la049959g Publication Date (Web): May 21, 2004 2004 The American Chemical Society (Non-Patent Document 2) describes a method for creating a photopolymerized PEG / phospholipid monolayer on a methacryloyl-terminated substrate.

US2009 / 0178934 (Patent Document 3) (Jarvius et al.) Covalently bond to the thermoplastic moiety defining the microfluidic recess, the junction layer on the thermoplastic moiety, and the junction layer to seal the microfluidic recess. It refers to a microfluidic structure including a siloxane elastomer moiety bonded to.

US2010 / 0207301 (Patent Document 4) (Suh et al.) Refers to a method of forming microchannels. This document states that a UV curable polymer pattern is formed on a first substrate and then the UV curable polymer pattern and the second substrate are encapsulated together by electrostatic attraction. Then, UV light is applied to form a channel.

US2013 / 0184631 (Patent Document 5) (Pinchuk) refers to a surgical kit containing at least one instrument and at least one device. This document states that the instrument has a needle body used for surgical passages through the ocular tissue. The document further states that the device includes a flexible tube that defines a duct for diversion of aqueous humor, with an outer surface having a maximum cross-sectional dimension that is smaller than the maximum cross-sectional dimension of the needle body.

WO 2014/207619 (Patent Document 6) (Delamarche et al.) Refers to how to make a package or assembly of a microfluidic chip with a separable chip.

U.S. Pat. No. 9,044,301 (Pinchuk et al.) Refers to a system that includes an elongated needle body and an aqueous humor drainage device.

US2003 / 0218130 US2004 / 0162545 US2009 / 0178934 US2010 / 0207301 US2013 / 0184631 International release WO2014 / 207619 U.S. Pat. No. 9,044,301

L.H. Sperling, "Interpenetrating Polymer Networks", (in Klempner et al., Advances in Chemistry; American Chemical Society: Washington, DC, 1994)) Kim et al., ("In Situ Photopolymerization of a Polymerizable Poly (ethylene glycol)-Covered Phospholipid Monolayer on a Methacryloyl-Terminated Substrate", 402-751, Korea Langmuir, 2004, 20 (13), pp 5396-5402 DOI: 10.1021 / la049959g Publication Date (Web): May 21, 2004 2004 American Chemical Society

Overview
In one aspect, (a) the steps of preparing first and second polymer articles with a polymer layer with a surface, respectively; (b) (i) solvent, (ii) radical formation initiator, and (iii) polymerizable. A step of contacting a component selected from the monomers and the surface so that each component is in contact with the surface of at least one polymer layer; (c) a step of contacting the surfaces of the polymer layers with each other; and (d) a graft polymer of the monomer. Together, including the step of initiating polymerization to produce, in which the graft polymer interpenetrates both polymer layers, thereby grafting the first polymer article onto the second polymer article. A method of grafting to is provided herein.

In one embodiment, the step of contacting the component with the surface is the step of contacting each surface with a solution containing the solvent and / or both of the radical-forming initiator and the polymerizable monomer, as well as the radical-forming initiator and the polymerizable monomer. Includes the step of infiltrating the polymer layer. In another aspect, the method further comprises the step of removing the solvent by evaporation (eg, vacuum or heating). In another aspect, the surface contacting step comprises applying the solvent to at least one surface, the applied solvent attracting the polymerizable monomer and radical initiator to the surface of the polymer layer. In another aspect, the polymer layer comprises a hydrogel. In another aspect, the polymer layer has biofouling protection properties. In another aspect, the polymer layer comprises poly-PEG acrylate, polyacrylamide, poly (glycerol), poly (2-oxazoline), poly (hydroxyfunctional acrylate), poly (vinylpyrrolidone), peptides, or peptoids. In another aspect, the polymer layer comprises the same or different polymers. In another aspect, the surface of at least one polymer layer comprises one or more microfeatures. In another aspect, at least one microfeature is a microchannel. In another aspect, the polymerizable monomer comprises polymerizable polyethylene glycol (“PEG”) (eg, acrylate-PEG-acrylate such as triethylene glycol dimethacrylate). In another aspect, the polymerizable monomer comprises zwitterions capable of free radical polymerization. In another embodiment, the polymerizable monomer is N- (2-methacryloyloxy) ethyl-N, N-dimethylammoniopropanesulfonate (“SPE”), N- (3-methacryloylumino) propyl-N, N-dimethylammoni. Includes propanesulfonate (“SPP”), 2- (methacryloyloxy) ethylphosphatidylcholine (“MPC”), or 3- (2'-vinyl-pyridinio) propanesulfonate (“SPV”). In another embodiment, the polymerizable monomer is poly (2-oxazoline) (eg, poly (2-ethyl-2-oxazoline)); poly (hydroxyfunctional acrylate) (eg, poly (2-hydroxyethylmethacrylate); poly). (Glycerol)); Poly (vinylpyrrolidone); contains peptides or peptides (eg, poly (amino acids) or poly (peptoids)). In another aspect, the polymerizable monomer comprises a plurality of different polymerizable monomers that polymerize to form a copolymer. In another aspect, the different polymerizable monomer comprises a heterodisperse polyethylene glycol monomer. In another aspect, the polymerizable monomer comprises acrylamide, acrylate, allyl, vinyl or styrene. In another embodiment, the radical formation initiator is a photoinitiator or a heat initiator. In another embodiment, the radical formation initiator is 2-hydroxy-2-methylpropiophenone, benzoin ether, benzyl ketal, a-dialkoxy-alkyl-phenone, a-hydroxy-alkyl-phenone, a-aminoalkyl-phenone. , Acyl-phosphine oxide, benzophenone, benzoamine, thioxanthone, thioamine and titanosen. In another embodiment, the radical formation initiator is tert-amylperoxybenzoate, 4-4-azobis (4-cyanovaleric acid), 1-1'azobis (cyclohexanecarbonitrile), 2-2'-azobisisobutyro. Nitrile, benzoyl peroxide, 2,2-bis (tert-butylperoxy) butane, 1,1-bis (tert-butylperoxy) cyclohexane, 2,5-bis (tert-butylperoxy) -2,5-dimethyl Hexane, 2,5-bis (tert-butylperoxy) -2,5-dimethyl-3-hexine, bis (1- (tert-butylperoxy) -1-methylethyl) benzene, 1,1-bis (tert) -Butyl Peroxy) -3,3,5-trimethyl Cyclohexane, tert-Butyl Hydroperoxide, tert-Butyl Peracetate, tert-Butyl Peroxide, tert-Butyl Peroxybenzoate, tert-Butyl Peroxyisopropyl Carbonate, Cumene Hydroperoxide , Cyclohexanone peroxide, dicumyl peroxide, lauroyl peroxide, 2,4-pentandione peroxide, peracetic acid and potassium persulfate. In another aspect, the polymer article comprises a solid substrate attached to the polymer.

Another aspect comprises the steps of (a) preparing the first and second articles containing the polymer layer bonded to the solid substrate, respectively; and (b) grafting the polymer layers together by the method described above. , A method of making a polymer device is provided herein. In one embodiment, the first article and / or the second article comprises a polymer layer covalently bonded to the substrate. In another aspect, the first article and / or the second article comprises a second polymer layer grafted onto an existing polymer layer. In another embodiment, the first article and the second article are prepared by a method comprising the following steps, respectively: (i) preparing a solid substrate containing a surface containing a polymerizable moiety; (ii) first polymerizable. The step of contacting the surface of the substrate with the composition containing the monomer and the radical formation initiator; and (iii) the step of initiating the polymerization to produce a polymer of the monomer, wherein the polymer is attached to the substrate via a polymerizable moiety. The process of covalent bonding. In another aspect, the polymer device comprises at least one microfeature, eg, a microchannel, placed on the grafted polymer layer. In another embodiment, the solid substrate is polyethylene terephthalate (“PET”), poly (methylmethacrylate) (“PMMA”), polyurethane (“PU”), polycarbonate (“PC”), polyvinyl chloride (“PVC”), Polyvinyl alcohol (“PVA”), polystyrene (“PS”), polyethylene (“PE”), polysulfone, polyethersulfone (“PES”), sulfonated polyethersulfone (“SPES”), polybutylene terephthalate (“PBT”) ”), Polyhydroxyalkanoate (“PHA”), silicone, parylene, polypropylene (“PP”), fluoropolymer, polyhydroxylethyl methacrylate (“pHEMA”), polyetherketoneketone (“PEKK”), polyetherether Ketone (“PEEK”), polyetheretherketone (“PAEK”), lactic acid / glycolic acid copolymer (“PLGA”), polytetrafluoroethylene (“PTFE”), or polyfluorovinylidene (“PVDF”) and polyacrylic acid. Contains substances selected from acid (“PAA”). In another embodiment, the polymerizable moiety comprises a C = C group (“sp2 hybrid carbon atom”). In another embodiment, the C = C group is a terminal acrylate group (eg, acryloxypropylsilane). In another aspect, the step of preparing the solid substrate comprises the step of functionalizing the polymer substrate with a hydroxyl group and the step of coupling (3-acryloxypropyl) trichlorosilane via the hydroxyl group. In another embodiment, the functionalizing step is to expose the surface to a physical or chemical treatment for surface hydroxyl activation (eg, plasma (eg, O2 plasma, air plasma, nitrogen plasma, H2 plasma, H2). + H2O plasma), including exposure to ozone, peroxide or piranha solution). In another aspect, the steps of preparing at least one article include preparing a mold with optionally one or more microfeatures, filling the mold with a composition, overlaying a solid substrate on the composition, It optionally includes a step of aligning the mold with the solid substrate and a step of initiating polymerization. In another aspect, the mold comprises silicon coated with polyvinyl alcohol (“PVA”), polydimethylsiloxane (“PDMS”), SU-8 epoxy, parylene, PTFE, dry film photoresist, or glass. In another aspect, the mold comprises a plurality of microfeature patterns in which each pattern corresponds to one of the plurality of microdevices. In another aspect, the method further comprises the step of separating the microfeatured chip (eg, by mechanical or laser cutting) to generate multiple microdevices. In another aspect, at least one microfeature is a microchannel, which has an inlet and an outlet that are open through the polymer, respectively. In another aspect, the microchannel has a length between about 0.5 mm and about 500 mm (eg, between about 2 mm and about 5 mm). In another aspect, the microdevice has an elongated shape. In another aspect, for at least one article, the composition further contacts the mold, which imparts microchannels to the polymer, whereby the final device comprises closed microchannels.

In another aspect, (a) a step of preparing a first article and a second article containing a polymer layer bonded to a substrate, respectively, wherein the polymer layer is partially cured; (b) first. The step of contacting the polymer of one article with the polymer of the second article; and (c) to covalently bond the articles through the polymerization of the monomers in the first and second articles to the common chain in the network polymer. Provided herein is a method of making a polymer device, comprising the step of initiating polymerization, wherein the first article is bonded to the second article. In one embodiment, the first and second articles are provided by a method comprising the following steps: (i) preparing a solid substrate containing a surface comprising a polymerizable moiety; (ii) polymerizable monomers and radicals. The step of contacting the surface of the substrate with the composition containing the formation initiator; and (iii) producing the monomer polymer over a period of time sufficient to initiate polymerization and sufficient time to produce a partially cured polymer of the monomer. A step of initiating polymerization for the purpose of covalently bonding a polymer to a substrate via a polymerizable portion. In another aspect, at least one of the articles comprises one or more microfeatures on the surface of the polymer. In another aspect, the first article and / or the second article comprises a polymer layer covalently bonded to the substrate. In another aspect, the first article and / or the second article comprises a polymer layer grafted onto the substrate.

In another aspect, (a) a step of preparing a first article containing a polymer layer bonded to a solid substrate, wherein the polymer layer is diffused onto the surface of the polymer layer, a polymerizable monomer and optionally a radical formation initiator. A step of preparing a second article containing a polymer layer bonded to a solid substrate, wherein the polymer layer is partially cured; and (c) in a network polymer. In order to covalently bond the articles through the polymerization of the polymerizable monomers in the first and second articles to the common chain of the first article, the polymer of the first article is brought into contact with the polymer of the second article to initiate polymerization. Provided herein is a method of making a polymeric device comprising joining a first article to a second article. In one embodiment, at least one of the first and second articles comprises one or more microfeatures on the surface of the polymer. In another embodiment, the steps of preparing the first and second articles are (a) (i) preparing a solid substrate containing a surface containing a polymerizable moiety; (ii) a polymerizable monomer and a radical formation initiator. Step of contacting the surface of the substrate with the composition comprising; (iii) Polymerization to produce a polymer of the monomer long enough to initiate polymerization and sufficient time to produce a partially cured polymer of the monomer. Preparation of the first article prepared by a method including a step of covalently bonding the polymer to the substrate via a polymerizable moiety, and (b) (i) polymerizable. Step of preparing a solid substrate containing a surface containing a moiety; (ii) a step of contacting the surface of the substrate with a composition containing a first polymerizable monomer and a radical formation initiator; (iii) to produce a polymer of the monomer. The step of initiating the polymerization, in which the polymer is covalently bonded to the substrate via a polymerizable moiety; and (iv) a second polymerizable monomer on the surface of the polymer and radicals on at least one article. The step of contacting with the formation initiator includes the step of preparing a second article prepared by a method including the step of diffusing the monomer and the initiator into the polymer. In another aspect, the first article and / or the second article comprises a polymer layer covalently bonded to the substrate. In another aspect, the first article and / or the second article comprises a second polymer layer grafted onto an existing polymer layer.

In another aspect, (a) the step of preparing a first polymer layer with a surface; (b) the step of contacting the surface with a radical formation initiator; (c) the step of contacting the surface with a polymerizable monomer; and (d). ) Provided herein is a method of grafting a second polymer layer onto a first polymer layer, comprising the step of initiating polymerization to produce a second polymer layer grafted onto the first polymer layer. In one embodiment, the radical initiator and the polymerizable monomer are applied simultaneously on the surface. In another aspect, the method further comprises applying a chemical to the surface prior to initiating the polymerization, the chemical being immobilized within the second polymer layer. In another embodiment, the radical initiator is diffused onto the surface prior to the step of contacting with the polymerizable monomer. In another embodiment, the chemical is applied with the polymerizable monomer and the chemical is immobilized within the second polymer layer. In another aspect, the method further comprises the step of removing the unpolymerized material from the surface.

In another aspect, a microfluidic device comprising a first layer and a second layer is provided herein, the first layer and the second layer each include a substrate to which the polymer layer is attached, the polymer layers bonded to each other. The device comprises one or more microfluidic channels penetrating the grafted polymer layer and opening through the port of the grafted polymer layer. In one embodiment, the layers are joined via a polymer network that interpenetrates the polymers of the first and second layers. In another aspect, the layers are covalently bonded. In another aspect, the microchannel comprises one or more features selected from columns, weirs, reservoirs, segment barriers, and walls. In another aspect, the device comprises multiple intersecting or non-intersecting microchannels. In another aspect, the device is in the form of a microshunt having a length dimension of about 1 mm to about 10 mm and a short dimension of about 0.1 mm to about 1 mm, and one or more microchannels traverse and lengthen the microshunt. It is open at the ports located at both ends of the dimension. In another aspect, the microchannel has a total resistance of 1e13 to 2.3e14Pa * s / mA3 (eg, a resistance of 2.5e13 to 4.5e13). In another aspect, the device comprises multiple microfluidic channels, the channel having an inlet on the same side of the device and an exit on the same side of the device. In another aspect, the polymer layer comprises a chemical entity or drug that can be eluted into the microchannel when the channel is filled with water.

In another aspect, a microshunt containing a non-bioadhesive polymer sandwiched between solid substrates made of biointegrated materials, wherein the polymer has a cross-sectional area of 100 square microns to 10,000 square microns and is from the polymer. Microshunts containing one or more microchannels with open inlets and outlets, the microshunt having an elongated shape with a length of about 0.5 mm to about 500 mm and a width of about 0.5 mm to about 10 mm. Is provided herein. In one embodiment, one or more microchannels are multiple microchannels. In another aspect, the microshunt comprises an aperture between the substrates. In another aspect, the microshunt is not tubular.

In another aspect, a method comprising the following steps is provided herein: (a) a body part containing a fluid, the device or microshunt described herein, at the entrance of the microchannel to the body. The step of inserting the part so that it is located inside the cavity and the outlet is located outside the body part; and (b) the step of draining the liquid from the body part via the microfluidic channel. In one embodiment, the device or shunt is an intraocular space, intracranial space, subcutaneous space, intraperitoneal space, intravesical space, peritoneal cavity, right atrium, pleural space, atrium, epicranial aponetic space, paranasal sinuses, It is inserted into the middle ear or the space inside the kidney. In another aspect, the device or shunt is inserted such that the inlet is located inside the body and the exit is located outside the body.

In another aspect, a method of treating glaucoma comprising the following steps is provided herein: (a) such that the entrance of the shunt is located in the intraocular space and the exit of the shunt is located outside the eye. A step of inserting a shunt into the eye, wherein the shunt comprises a laminated structure having a hard layer made of a biocompatible material and an internal polymer layer, wherein the internal polymer layer is a hydrogel having anti-bioadhesive properties. A step comprising the inlet and at least one channel communicating with the exit through the polymer layer; and (b) draining the liquid from the inside of the eye to the outside of the eye.
[Invention 1001]
(a) Steps of preparing first and second polymer articles each having a polymer layer with a surface;
(B) A step of contacting the surface of a component selected from (i) a solvent, (ii) a radical formation initiator, and (iii) a polymerizable monomer so that each component is in contact with the surface of at least one polymer layer. ;
(c) Steps to bring the surfaces of the polymer layers into contact with each other;
(d) A step of initiating polymerization to produce a graft polymer of a monomer, in which the graft polymer interpenetrates both polymer layers, thereby grafting the first polymer article to the second polymer article.
A method of grafting two polymer articles together, including.
[Invention 1002]
The step of contacting the components with the surface is the step of contacting each surface with a solution containing the solvent and one or both of the radical formation initiator and the polymerizable monomer, and the radical formation initiator and the polymerizable monomer penetrate into the polymer layer. The method of the present invention 1001 comprising the step of causing.
[Invention 1003]
The method of the present invention 1002, further comprising the step of removing the solvent by evaporation resulting from heating or applying a vacuum.
[Invention 1004]
The method of the invention 1001 wherein the surface contacting step comprises applying the solvent to at least one surface, wherein the applied solvent attracts the polymerizable monomer and radical initiator to the surface of the polymer layer.
[Invention 1005]
The method of the present invention 1001 wherein the polymer layer comprises a hydrogel.
[Invention 1006]
The method of the present invention 1001 in which the polymer layer has biofouling-preventing properties.
[Invention 1007]
The method of the present invention 1001 wherein the polymer layer comprises poly-PEG acrylate, polyacrylamide, poly (glycerol), poly (2-oxazoline), poly (hydroxyfunctional acrylate), poly (vinylpyrrolidone), peptide, or peptoid. ..
[Invention 1008]
The method of the present invention 1001 wherein the polymer layer comprises the same or different polymers.
[Invention 1009]
The method of the present invention 1001 wherein the surface of at least one polymer layer comprises one or more microfeatures.
[Invention 1010]
The method of the present invention 1009, wherein at least one microfeature is a microchannel.
[Invention 1011]
The method of the present invention 1001 wherein the polymerizable monomer comprises polymerizable polyethylene glycol (“PEG”).
[Invention 1012]
The method of the present invention 1011, wherein the polymerizable polyethylene glycol comprises triethylene glycol dimethacrylate.
[Invention 1013]
The method of the present invention 1001 wherein the polymerizable monomer contains zwitterions capable of free radical polymerization.
[Invention 1014]
Polymerizable monomers are N- (2-methacryloyloxy) ethyl-N, N-dimethylammoniopropanesulfonate (“SPE”), N- (3-methacryloylumino) propyl-N, N-dimethylammoniopropanesulfonate ("SPE"). The method of the present invention 1001 comprising "SPP"), 2- (methacryloyloxy) ethylphosphatidylcholine ("MPC"), or 3- (2'-vinyl-pyridinio) propanesulfonate ("SPV").
[Invention 1015]
The polymerizable monomer is poly (2-oxazoline) (eg, poly (2-ethyl-2-oxazoline)); poly (hydroxyfunctional acrylate) (eg, poly (2-hydroxyethylmethacrylate); poly (glycerol)). Poly (vinylpyrrolidone); the method of the present invention 1001 comprising a peptide or peptoid (eg, poly (amino acid) or poly (peptoid)).
[Invention 1016]
The method of the present invention 1015, wherein the poly (2-oxazoline) comprises poly (2-hydroxyethyl methacrylate).
[Invention 1017]
The method of the present invention 1001, wherein the polymerizable monomer comprises a plurality of different polymerizable monomers that polymerize to form a copolymer.
[Invention 1018]
The method of the present invention 1017, wherein the different polymerizable monomers comprises a heterodisperse polyethylene glycol monomer.
[Invention 1019]
The method of the present invention 1001 wherein the polymerizable monomer comprises acrylamide, acrylate, allyl, vinyl or styrene.
[Invention 1020]
The method of the present invention 1001 wherein the radical formation initiator is a photoinitiator or a heat initiator.
[Invention 1021]
Radical formation initiators are 2-hydroxy-2-methylpropiophenone, benzoin ether, benzyl ketal, α-dialkoxy-alkyl-phenone, α-hydroxy-alkyl-phenone, α-aminoalkyl-phenone, acyl-phosphine. The method of the present invention 1001, which is a photoinitiator selected from oxides, benzophenones, benzoamines, thioxanthones, thioamines and titanosen.
[Invention 1022]
Radical formation initiators are tert-amylperoxybenzoate, 4-4-azobis (4-cyanovaleric acid), 1-1'-azobis (cyclohexanecarbonitrile), 2-2'-azobisisobutyronitrile, benzoyl. Peroxide, 2,2-bis (tert-butylperoxy) butane, 1,1-bis (tert-butylperoxy) cyclohexane, 2,5-bis (tert-butylperoxy) -2,5-dimethylhexane, 2,5-bis (tert-butylperoxy) -2,5-dimethyl-3-hexine, bis (1- (tert-butylperoxy) -1-methylethyl) benzene, 1,1-bis (tert-butyl) Peroxy) -3,3,5-trimethylcyclohexane, tert-butyl hydroperoxide, tert-butyl peroxide, tert-butyl peroxide, tert-butyl peroxybenzoate, tert-butyl peroxyisopropyl carbonate, cumene hydroperoxide, cyclohexanone The method of the present invention 1001, which is a heat initiator selected from peroxides, dicumyl peroxides, lauroyl peroxides, 2,4-pentandion peroxides, peracetic acid and potassium persulfate.
[Invention 1023]
The method of the present invention 1001 wherein the polymer article comprises a solid substrate bonded to the polymer.
[Invention 1024]
(a) Steps of preparing the first and second articles containing the polymer layer bonded to the solid substrate, respectively;
(b) Step of grafting polymer layers together by the method of the present invention 1001
A method of making a polymer device, including.
[Invention 1025]
The method of 1024 of the present invention, wherein the first article and / or the second article comprises a polymer layer covalently bonded to a substrate.
[Invention 1026]
The method of 1024 of the present invention, wherein the first article and / or the second article comprises a second polymer layer grafted onto an existing polymer layer.
[Invention 1027]
The first article and the second article
(i) Step of preparing a solid substrate containing a surface containing a polymerizable moiety;
(ii) A step of contacting the surface of the substrate with the composition containing the first polymerizable monomer and the radical formation initiator;
(iii) A step of initiating polymerization to produce a polymer of a monomer, in which the polymer is covalently bonded to a substrate via a polymerizable moiety.
The method of the present invention 1024, each prepared by a method comprising:
[Invention 1028]
The method of 1024 of the present invention, wherein the polymer device comprises at least one microfeature placed on the grafted polymer layer.
[Invention 1029]
Solid substrates include polyethylene terephthalate (“PET”), poly (methylmethacrylate) (“PMMA”), polyurethane (“PU”), polycarbonate (“PC”), polyvinyl chloride (“PVC”), and polyvinyl alcohol (“PVC”). PVA ”), polystyrene (“PS”), thermoplastic polyurethane (“TPU”), polyethylene (“PE”), polysulfone, polyethersulfonate (“PES”), sulfonated polyethersulfone (“SPES”), poly Butylene terephthalate ("PBT"), polyhydroxyalkanoate ("PHA"), silicone, parylene, polypropylene ("PP"), fluoropolymer, polyhydroxylethylmethacrylate ("pHEMA"), polyetherketoneketone ("PEKK") ), Polyetheretherketone (“PEEK”), Polyetheretherketone (“PAEK”), Lactic / glycolic acid copolymer (“PLGA”), Polytetrafluoroethylene (“PTFE”), Polyfluorinated vinylidene (“PVDF”) ), And the method of the present invention 1024 comprising a substance selected from polyacrylic acid (“PAA”).
[Invention 1030]
The method of 1024 of the present invention, wherein the polymerizable moiety contains a C = C group (“sp2 hybrid carbon atom”).
[Invention 1031]
The method of the present invention 1030, wherein the C = C group is the terminal acrylate group.
[Invention 1032]
The method of 1024 of the present invention, wherein the step of preparing the solid substrate comprises the step of functionalizing the polymer substrate with a hydroxyl group and the step of coupling (3-acryloxypropyl) trichlorosilane via a hydroxyl group.
[Invention 1033]
The method of 1024 of the present invention, wherein the functionalizing step comprises exposing the surface to a physical or chemical treatment for surface hydroxyl activation.
[Invention 1034]
The steps of preparing at least one article include preparing a mold with optionally one or more microfeatures, filling the mold with a composition, overlaying a solid substrate on the composition, and optionally a mold and a solid. The method of the present invention 1024 comprising a step of aligning with a substrate and a step of initiating polymerization.
[Invention 1035]
The method of the invention 1024, wherein the mold comprises polyvinyl alcohol (“PVA”) coated silicon, polydimethylsiloxane (“PDMS”), SU-8 epoxy, parylene, PTFE, dry film photoresist, or glass.
[Invention 1036]
The method of the invention 1024, wherein the mold contains a plurality of microfeature patterns, each pattern corresponding to one of a plurality of microdevices.
[Invention 1037]
The method of 1024 of the present invention further comprising the step of separating the chip with microfeatures to generate a plurality of microdevices.
[Invention 1038]
The method of 1024 of the invention, wherein at least one microfeature is a microchannel, the microchannel having an inlet and an outlet each opening through the polymer.
[Invention 1039]
The method of the present invention 1038, wherein the microchannel has a length of about 0.5 mm to about 500 mm.
[Invention 1040]
The method of the present invention 1039, wherein the microchannel has a length of about 2 mm to about 5 mm.
[Invention 1041]
The method of the present invention 1024, wherein the microdevice has an elongated shape.
[Invention 1042]
The method of 1024 of the present invention, wherein for at least one article, the composition further contacts the mold, the mold imparting microchannels to the polymer, whereby the final device comprises closed microchannels.
[Invention 1043]
(a) A step of preparing a first article and a second article containing a polymer layer bonded to a substrate, respectively, wherein the polymer layer is partially cured; and
(b) The step of bringing the polymer of the first article into contact with the polymer of the second article;
(c) A step of initiating polymerization to covalently bond the articles through the polymerization of the monomers in the first and second articles to the common chain in the network polymer, where the first article is the second article. The process of joining to an article
A method of making a polymer device, including.
[Invention 1044]
The first article and the second article
(i) Step of preparing a solid substrate containing a surface containing a polymerizable moiety;
(ii) The step of contacting the surface of the substrate with the composition containing the polymerizable monomer and the radical formation initiator;
(iii) A step of initiating polymerization to produce a polymer of a monomer over a period of time sufficient to initiate polymerization and sufficient time to produce a partially cured polymer of the monomer, wherein the polymer is a polymerizable moiety. The process of covalently bonding to the substrate via
The method of the present invention 1043, which is prepared by a method comprising.
[Invention 1045]
The method of the invention 1044, wherein at least one article comprises one or more microfeatures on the surface of the polymer.
[Invention 1046]
The method of 1043 of the present invention, wherein the first article and / or the second article comprises a polymer layer covalently bonded to a substrate.
[Invention 1047]
The method of 1043 of the present invention, wherein the first article and / or the second article comprises a polymer layer grafted onto a substrate.
[Invention 1048]
(a) A step of preparing a first article containing a polymer layer bonded to a solid substrate, wherein the polymer layer comprises a polymerizable monomer and optionally a radical formation initiator diffused on the surface of the polymer layer. ;
(b) A step of preparing a second article containing a polymer layer bonded to a solid substrate, wherein the polymer layer is partially cured;
(c) The polymer of the first article is covalently bonded to the polymer of the second article in order to covalently bond the articles through the polymerization of the polymerizable monomers in the first and second articles to the common chain in the network polymer. A step of contacting and initiating polymerization, in which the first article is bonded to the second article.
A method of making a polymer device, including.
[Invention 1049]
The method of the invention 1048, wherein at least one of the first and second articles comprises one or more microfeatures on the surface of the polymer.
[Invention 1050]
The process of preparing the first and second articles is
(a) (i) Step of preparing a solid substrate containing a surface containing a polymerizable moiety;
(ii) A step of contacting the surface of the substrate with the composition containing the polymerizable monomer and the radical formation initiator;
(iii) A step of initiating polymerization to produce a polymer of a monomer over a period of time sufficient to initiate polymerization and sufficient time to produce a partially cured polymer of the monomer, wherein the polymer is a polymerizable moiety. The process of covalently bonding to the substrate via
And the process of preparing the first article prepared by the method including
(b) (i) Step of preparing a solid substrate containing a surface containing a polymerizable moiety;
(ii) A step of contacting the surface of the substrate with the composition containing the first polymerizable monomer and the radical formation initiator;
(iii) A step of initiating polymerization to produce a polymer of monomers, wherein the polymer is covalently bonded to a substrate via a polymerizable moiety;
(iv) The step of contacting the surface of the polymer with the second polymerizable monomer and the radical formation initiator on at least one article, wherein the monomer and the initiator diffuse into the polymer.
And the process of preparing a second article prepared by a method comprising
The method of the present invention 1048, comprising.
[Invention 1051]
The method of the present invention 1048, wherein the first article and / or the second article comprises a polymer layer covalently bonded to a substrate.
[Invention 1052]
The method of the invention 1048, wherein the first article and / or the second article comprises a second polymer layer grafted onto an existing polymer layer.
[Invention 1053]
(a) Step of preparing the first polymer layer having a surface;
(b) Step of contacting the surface with the radical formation initiator;
(c) Step of contacting the surface with the polymerizable monomer; and
(d) Step of initiating polymerization to form a second polymer layer grafted on the first polymer layer
A method of grafting a second polymer layer onto a first polymer layer, including.
[Invention 1054]
The method of the present invention 1053, wherein the radical initiator and the polymerizable monomer are simultaneously applied to the surface.
[Invention 1055]
The method of the present invention 1054, further comprising applying a chemical to the surface prior to initiating polymerization, wherein the chemical is immobilized in a second polymer layer.
[Invention 1056]
The method of the present invention 1053, wherein the radical initiator is diffused onto the surface prior to the step of contacting it with the polymerizable monomer.
[Invention 1057]
The method of the invention 1055, wherein the chemical is applied with the polymerizable monomer and the chemical is immobilized in the second polymer layer.
[Invention 1058]
The method of the present invention 1053, further comprising the step of removing unpolymerized material from the surface.
[Invention 1059]
A microfluidic device comprising a first layer and a second layer containing a substrate to which the polymer layers are bonded, respectively, wherein the polymer layers are bonded to each other and the device penetrates and is grafted through the grafted polymer layer. A microfluidic device that contains one or more microfluidic channels that are open through a port in a polymer layer.
[Invention 1060]
The device of the present invention 1059, wherein the layers are joined via a polymer network that interpenetrates the polymers of the first and second layers.
[Invention 1061]
The device of the present invention 1059, in which the layers are covalently bonded.
[Invention 1062]
The device of the invention 1059, wherein the microchannel comprises one or more features selected from columns, weirs, reservoirs, segment barriers, and walls.
[Invention 1063]
The device of the invention 1059, including multiple crossed or non-crossed microchannels.
[Invention 1064]
It has the form of a microshunt with a length of about 1 mm to about 10 mm and a short size of about 0.1 mm to about 1 mm, with one or more microchannels traversing the microshunt and located at both ends of the length. The device of the invention 1059 that is open at the port.
[Invention 1065]
The device of the present invention 1059, wherein the microchannel has a total resistance of 1e13 to 2.3e14Pa * s / m ^ 3.
[Invention 1066]
The device of the present invention 1059, wherein the microchannel has a total resistance of 2.5e13 to 4.5e13.
[Invention 1067]
The device of the invention 1059 comprising a plurality of microfluidic channels, the channel having an inlet on the same side of the device and an outlet on the same side of the device.
[Invention 1068]
The device of the invention 1059, wherein the polymer layer comprises a chemical entity or drug that can be eluted into the microchannel when the channel is filled with water.
[Invention 1069]
A microshunt containing a non-bioadhesive polymer sandwiched between solid substrates made of biointegrated materials, wherein the polymer has a cross-sectional area of 100 square microns to 10,000 square microns and is open from the polymer. A microshunt comprising one or more microchannels with inlets and outlets, wherein the microshunt has an elongated shape with a length of about 0.5 mm to about 500 mm and a width of about 0.5 mm to about 10 mm.
[Invention 1070]
The microshunt of the present invention 1069, wherein one or more microchannels are multiple microchannels.
[Invention 1071]
Microshunt of the present invention 1069, comprising an aperture between the substrates.
[Invention 1072]
The microshunt of the present invention 1069, which is not tubular.
[Invention 1073]
(a) The device of the invention 1059 or the microshunt of the invention 1069 is placed on a body part containing fluid, with the inlet of the microchannel located inside the cavity of the body part and the exit located outside the body part. The process of inserting; and
(b) The process of draining liquid from a body part via a microfluidic channel
Including the method.
[Invention 1074]
The device or shunt can be an intraocular space, an intracranial space, a subcutaneous space, an intraperitoneal space, an intravesical space, a peritoneal cavity, the right atrium, a pleural space, a large cistern, an epicranial submembrane space, a paranasal sinus, the middle ear, or The method of the present invention 1073, which is inserted into the intrarenal space.
[Invention 1075]
The method of the invention 1073, wherein the device or shunt is inserted such that the entrance is located inside the body and the exit is located outside the body.
[Invention 1076]
(a) The step of inserting the shunt into the eye so that the entrance of the shunt is located in the intraocular space and the exit of the shunt is located outside the eye, and the shunt is a hard layer made of a biocompatible material. A step comprising a laminated structure with an internal polymer layer, wherein the internal polymer layer comprises a hydrogel having bioadhesion resistant properties and at least one channel that penetrates the polymer layer and communicates with the inlet and outlet. ;and
(b) The process of draining the liquid from the inside of the eye to the outside of the eye
How to treat glaucoma, including.

The steps in the manufacture of the microfluidic device of the present disclosure are shown. A method of functionalizing a solid PET substrate with silane is shown. A method of functionalizing a PET surface with a functionalized silane is shown. The method of making the silicon mold coated with polyvinyl alcohol is shown. The method of making a PDMS mold is shown. It indicates the initiation of polymerization in which the photoinitiator 2-hydroxy-2-methylpropiophenone forms an intermediate with triethylene glycol dimethacrylate. It shows a coupling reaction in which acrylic silane bonded to the PET surface and PEG dimethacrylate polymerize. The crosslinked polymers described herein are covalently bonded to the PET surface by a polymerization reaction. A method of making two polymer articles lined with a substrate and joining the two articles with an interpenetrating network polymer is shown. A method of making two polymer articles lined with a substrate and partially cured and joining the two articles by curing is shown. A method of grafting a polymerizable monomer on the surface of a substrate, in which a photoinitiator is interpenetrated into the substrate before UV photopolymerization, is shown. Demonstrates a method of grafting a polymerizable monomer onto the surface of a polymer layer of a polymer article, in which a photoinitiator and a monomer are interpenetrated into a substrate and a solvent is used to attract the diffused monomer and the photoinitiator to the surface. A method of grafting a second polymerizable monomer on the surface of a partially cured polymer article is shown. The pattern of the mold for making eight microdevices on a single polymer device is shown. The drawings also show the device obtained after disconnection from the masterpiece. An exploded view of the water drain device is shown. The device contains two PEG polymer layers, each lined with a layer of PET. One of the PEG layers contains microfeatures, which in this case are microchannels. Bonding the PEG layers together seals the channel. 16A and 16B show two forms of the microshunt of the present disclosure. Both are chip-shaped and have two microchannels open at both ends of the chip. In addition, each device includes an aperture that penetrates the device to facilitate biointegration. The flow chart of the aqueous humor dynamics by the brown glaucoma implant is shown. Shows intraocular pressure as a function of flow rate.

Detailed explanation
I. Introduction This disclosure provides polymer articles (devices) with microfeatures and methods for making and using them.

The particular polymer device of the present disclosure is a microfluidic device configured to function as a water drainage device. Such devices may have a sandwich configuration in which the polymer layer is sandwiched between two solid substrate layers. The polymer layer has one or more inlets and one or more outlets located at both ends of the sandwich. The inlet and outlet communicate with each other via microfluidic channels arranged in the polymer layer. The polymer layer can be attached to the substrate layer via various methods. The polymer layer itself can be formed from two initial polymer layers bonded together by various methods, including for example grafting or curing a partially cured polymer layer. In certain embodiments, the substrate layer comprises a bioincorporated material and the polymer layer has biofouling-preventing properties. Such devices can be inserted into body parts and used as microshunts to transport liquid from one location to another. In one embodiment, the body part is the eye and the device drains fluid from the inside of the eye to the outside of the eye.

The present disclosure also provides a method of joining a first polymer to a second polymer. In one embodiment, the method of joining the first polymer article to the second polymer article involves grafting with an interpenetrating polymer network. Usually, the polymerizable monomer and radical initiator penetrate the surface of one or both polymers. A solvent may then be used to attract the polymerizable monomer and radical initiator to the surface. Polymerization begins when the surfaces of the polymers come into contact with each other. For example, the radical formation initiator can be a photoinitiator. Polymerization can be initiated by exposure to light. Polymerization of the polymerizable monomer creates a crosslinked polymer network that interpenetrates both polymer articles, thereby joining the polymer articles together. If the surface of one or both polymer articles contains microfeatures such as microchannels, this method seals the closed microfeatures without gaps between the polymer layers and without deforming the shape of the microfeatures. Produces a rigid bond.

Another method of joining two polymer articles together involves creating two partially cured polymer articles, contacting the surfaces of the two articles and completing the curing process. This produces a polymer layer that is directly bonded to each other.

The methods of the present disclosure are useful for joining polymer articles together for any purpose or for the final device, eg, for grafting. The devices of the present disclosure can also be made by methods other than joining the two polymer layers together. For example, polymeric articles that may or may not be molded as layers and may or may not be bonded to the substrate themselves may be joined together by the methods disclosed herein. Similarly, microfeatures such as channels can be introduced into the polymer by another method such as 3D laser etching.

The methods and articles of the present disclosure will be described in more detail by way of example.

II. Methods of Making Polymer Articles The particular polymer articles of the present disclosure are configured as sandwiches comprising an outer substrate layer and an inner polymer layer. The substrate layer is bonded to the polymer layer, and the polymer layers containing microfeatures such as microchannels are bonded to each other. The present disclosure provides a plurality of different methods for attaching a substrate to a polymer and attaching the polymers to each other. These methods can be combined in the production of a single article.

The method of binding the substrate to the polymer comprises, but is not limited to, (1) a step of covalently bonding the polymer to the surface of the substrate via a polymerizable moiety and (2) a step of diffusion grafting. The method of bonding the polymer layers to each other includes, but is not limited to, (1) grafting and (2) curing the partially cured layer.

A. Polymers The polymers used in the methods and devices of the present disclosure can be any polymer material suitable for the application. In certain embodiments, the polymer is hydrogel. Hydrogel is a water-insoluble network polymer in which water is dispersed to some extent throughout. Such networks are suitable for intrusion by monomers that can form interpenetrating polymer networks. The hydrogel can be, but is not limited to, polyPEG acrylate or polyacrylamide.

The devices of the present disclosure may include two polymer layers bonded together and lined with a substrate. The polymer in either of the two articles can be the same polymer or different polymers. The polymer can be a homopolymer or a copolymer.

The "polymerizable monomer" refers to a monomer having a polymerizable moiety. The polymer can be formed by polymerizing a polymerizable monomer. The "polymerizable moiety" refers to a chemical moiety capable of causing a polymerization reaction. The polymerizable moiety may contain a C = C group (“sp2 hybrid carbon atom”). Examples of polymerizable moieties include compounds with terminal ethylene groups, such as acrylates (eg, methacrylates, acrylamides, etc.). Examples of polymerizable monomers include PEG acrylate. A polymerizable monomer having a plurality of polymerizable moieties can form a crosslinked polymer. Therefore, dimethacrylate monomers are useful in the polymers described herein.

The polymerizable monomer contains, but is not limited to, PEG-acrylate, acrylamide, acrylate, allyl, vinyl or styrene. In one embodiment, the polymerizable monomer may include polymerizable polyethylene glycol (“PEG”) such as acrylate-PEG-acrylate. For example, PEG monomers having 3, 4, 5, 6, 7, 8 or 9 ethylene groups, such as triethylene glycol dimethacrylate, are useful. The polymerizable monomer may contain zwitterions capable of free radical polymerization. Polymerizable monomers are N- (2-methacryloyloxy) ethyl-N, N-dimethylammoniopropanesulfonate (“SPE”), N- (3-methacryloylimino) propyl-N, N-dimethylammoniopropanesulfonate (“SPE”). SPP "), 2- (methacryloyloxy) ethylphosphatidylcholine ("MPC "), and 3- (2'-vinyl-pyridinio) propanesulfonate ("SPV ")).

In some embodiments, the polymerizable monomer comprises a heterodisperse polyethylene glycol monomer. For example, the monomer may contain triethylene glycol dimethacrylate and a higher molecular weight PEG (PEGMA, Mn = 500), for example in a ratio of 5: 1 to 20: 1, for example about 9: 1. By adjusting the ratio, one of ordinary skill in the art can adjust the physical properties of the polymer (eg, durometer, swelling ratio, flexibility, modulus, etc.). This two-component polymer solution may impart greater biofouling protection properties. In another aspect, the polymerizable monomer may further comprise a heterobifunctional monomer such as PEG-methacrylate.

Polymerization typically requires a radical formation initiator. The radical formation initiator can be, for example, a photoinitiator or a heat initiator. Photoinitiators include, for example, 2-hydroxy-2-methylpropiophenone, benzoin ether, benzyl ketal, α-dialkoxy-alkyl-phenone, α-hydroxy-alkyl-phenone, α-aminoalkyl-phenone, acyl-. Includes phosphine oxide, benzophenone, benzoamine, thioxanthone, thioamine and titanosen. The heat initiators are, for example, tert-amylperoxybenzoate, 4-4-azobis (4-cyanovaleric acid), 1-1'-azobis (cyclohexanecarbonitrile), 2-2'-azobisisobutyronitrile, Benzoyl peroxide, 2,2-bis (tert-butylperoxy) butane, 1,1-bis (tert-butylperoxy) cyclohexane, 2,5-bis (tert-butylperoxy) -2,5-dimethylhexane , 2,5-bis (tert-butylperoxy) -2,5-dimethyl-3-hexine, bis (1- (tert-butylperoxy) -1-methylethyl) benzene, 1,1-bis (tert- Butyl Peroxy) -3,3,5-trimethyl Cyclohexane, tert-butyl Hydroperoxide, tert-Butyl Peracetate, tert-Butyl Peroxide, tert-Butyl Peroxybenzoate, tert-Butyl Peroxyisopropyl Carbonate, Cumene Hydroperoxide, Includes cyclohexanone peroxide, dicumyl peroxide, lauroyl peroxide, 2,4-pentandione peroxide, peracetic acid, potassium persulfate.

Thus, a solution containing a polymerizable monomer and a radical formation initiator produces a covalently coupled polymer on the surface of the substrate when contacted with the functionalized substrate and subjected to polymerization.

B. Substrate Prepare the substrate that forms the outer layer of the sandwich, the lining. The substrate is solid and typically rigid. For example, solid substrates include polyethylene terephthalate (“PET”), poly (methylmethacrylate) (“PMMA”), thermoplastic polyurethane (“TPU”), polyurethane (“PU”), polycarbonate (“PC”), and polychloride. Vinyl (“PVC”), Polyvinyl Alcohol (“PVA”), Polystyrene (“PS”), Polyethylene (“PE”), Polysulfone, Polyetherketone (“PES”), Sulfated Polyetherketone (“SPES”) , Polybutylene terephthalate ("PBT"), polyhydroxyalkanoate ("PHA"), silicone, parylene, polypropylene ("PP"), fluoropolymer, polyhydroxylethylmethacrylate ("pHEMA"), polyetherketoneketone ("" PEKK ”), Polyetheretherketone (“PEEK”), Polyetheretherketone (“PAEK”), Lactic Acid / Glycolic Acid Polymer (“PLGA”), Polytetrafluoroethylene (“PTFE”), or Polyfluorovinylidene (“PTFE”) It may contain a substance selected from "PVDF") and polyacrylic acid ("PAA").

C. Mold Polymerization can proceed on the mold. First and second molds into which the polymer is molded may be prepared. The mold may include a solid material from which the polymer can be removed after molding. Such materials include, for example, silicon, polydimethylsiloxane (“PDMS”), SU-8 epoxy, parylene, PTFE, dry film photoresist, or glass. The mold may be coated with a lubricant to aid in the removal of the polymer. For example, the lubricant can be polyvinyl alcohol (“PVA”). One or both of the molds may have one or more microfeatures conferred on the polymer on its surface. "Microfeature" refers to a feature that has dimensions of 1000 microns or less in one aspect. Microfeatures can be, for example, microchannels or compartments. Therefore, a microfluidic channel refers to a fluid channel having an aspect such as diameter of 1000 microns or less. Microchannels can include one or more features, such as columns, weirs, reservoirs, segment barriers and walls. The microfeatures on the mold can be the inside out of the feature to be given. So, for example, by adding material to the surface (eg, raised ridges) or by etching the surrounding valleys (grooves defining the ridges in between), by including the ridges on the mold. The polymer can be channeled. In some embodiments, the mold comprises a plurality of microfeature patterns, each corresponding to one of the plurality of microdevices.

In another aspect, the feature is a macro feature, that is, a feature that does not have dimensions less than 1000 μm.

The method for producing the polymer article includes a step of filling a mold with a solution containing a polymerizable monomer and a radical formation initiator, a step of superimposing a solid substrate containing a polymerizable portion on its surface, and optionally a mold and a solid substrate. It may include a step of aligning with and a step of initiating polymerization.

After the polymerization is complete, the polymer article, which in this case contains both the polymer layer and the backing of the solid substrate, can be removed from the mold. The two articles can then be joined together using the methods described herein, for example, via grafting with an interpenetrating polymer network.

The mold may include a silicon wafer having a diameter of 2 inches to 16 inches, for example about 4 inches. Alternatively, the mold may consist of a pattern layer of PDMS on a glass substrate measuring 1 to 12 inches in diameter and 2 to 16 inches in width, eg, 4 inches x 4 inches.

III. Bonding of polymer to substrate
A. Covalent bonding of the polymer to a substrate with a surface having a polymerizable moiety
1. Fully Cured Polymer Articles The particular polymer articles of the present disclosure include a polymer layer bonded to a substrate layer via a polymerization reaction. For this purpose, a substrate having a surface containing a polymerizable moiety is prepared.

The surface of the solid substrate does not have to contain the polymerizable portion from the beginning. In this case, the surface can be functionalized to incorporate such portions. For example, the polymer substrate can be functionalized with a hydroxyl group and the polymerizable moiety and the molecule can be coupled via the hydroxyl group. Functionalization can include exposing the surface to physical or chemical treatment for surface hydroxyl activation (eg, O ₂ plasma, air plasma, nitrogen plasma, H ₂ plasma, H ₂ + H ₂ O plasma). Exposure to), ozone, peroxide or piranha solution.

In one embodiment, a silane having a terminal C = C (eg, an acryloxyalkylsilane) is coupled to the surface via a hydroxyl group. In this way, the polymerizable acrylate group is provided on the surface of the substrate. One compound useful for surface functionalization at the polymerizable moiety is 3-acryloxypropyltrichlorosilane.

In this method, the surface of the mold is coated with a solution containing the polymerizable monomer and the radical formation initiator. The mold is coated with a substrate so that the surface containing the polymerizable moiety is in contact with the polymerizable solution. Then, the polymerization is started and the polymerizable monomers are coupled to each other and to the polymerizable monomer on the surface of the substrate. The resulting polymer article is then removed from the mold.

2. Partially Cured Polymer Articles Another method for producing polymer articles for joining together is to form an article with a partially cured polymer, to bring the articles into contact, and then both. It involves the step of completing the polymerization so that the monomers in the pieces polymerize with each other, thereby joining the two pieces together. Such a method may include the steps of preparing the first and second articles, each of which is prepared by a method comprising the following steps: (i) comprising a polymerizable moiety: Steps to prepare a solid substrate containing a surface; (ii) a step of contacting the surface of the substrate with a composition containing a polymerizable monomer and a radical formation initiator; and (iii) sufficient and partial monomer to initiate polymerization. A step of initiating polymerization to produce a polymer of monomers over a period of time sufficient to produce a polymer cured to, wherein the polymer is covalently bonded to a substrate via a polymerizable moiety; At least one article contains one or more microfeatures on the surface of the polymer.

The use of substrate lining, moldings, polymerizable moieties and radical initiators can be similar to those described above in the production of fully cured polymers.

B. Binding of Polymer to Polymer Articles by Diffusion Bonding In another embodiment, the second polymer layer is bonded to the first polymer layer already bonded to the substrate. In general, this allows a second polymerizable monomer, which may be the same as or different from the first polymerizable monomer already polymerized on and attached to the substrate, to be diffused into the polymer and polymerized, for example, to a cured state. , Thereby forming a layer that coats the surface.

FIG. 11 shows an exemplary method of adding a second polymer layer to an existing layer of polymer article. Prepare the polymer article (1). In this case, a radical formation initiator, which is a photoinitiator, is applied to the surface and diffused to the surface (2). Polymerizable monomers (“graft chemicals”) are applied to the surface (3). Then, in this case, exposure to UV light initiates polymerization (4). This results in the grafting of the second polymer layer onto the first polymer layer. Unpolymerized monomers are removed by washing (5).

FIG. 12 shows another exemplary method of adding a second polymer layer to an existing layer of polymer article. In this method, both the radical initiator and the polymerizable monomer are diffused onto the surface of the existing polymer layer (2). The surface is then washed and a solvent is applied to the surface to attract the polymerizable monomer and radical initiator to the surface of the article (3). Polymerization is initiated, for example by exposure to UV light (4). This results in a graft of the second polymer layer onto the surface. Unpolymerized monomers are removed by washing (5).

IV. Joining Polymer Articles Together The present disclosure also provides a method of joining polymer articles together. These methods can be used for the manufacture of the devices disclosed herein. The method can also be used to join together another polymer article for another purpose, eg, a polymer article containing a polymer layer that is not bonded to the backing of a substrate.

A. Grafting Polymers with Interpenetrating Polymer Networks The method of grafting polymer articles together creates a polymer network that interpenetrates the polymers of different polymer articles, thereby joining the articles together.

In one embodiment, the method of grafting two polymer articles together comprises the following steps: (a) preparing first and second polymer articles each having a polymer layer with a surface; (b) (i). A step of contacting a component selected from a solvent, (ii) a radical formation initiator, and (iii) a polymerizable monomer so that each component is in contact with the surface of at least one polymer layer; (c) polymer. The step of bringing the surfaces of the layers into contact with each other; as well as (d) the step of initiating the polymerization to produce a graft polymer of the monomer, in which the graft polymers interpenetrate both polymer layers and second the first polymer article. The process of grafting onto a polymer article.

The radical initiator and the polymerizable monomer are prepared in a solution containing a solvent. The solution is applied to the surface of both polymers to penetrate the surface of the polymer. The solvent can then be removed, for example, by evaporation or by heating. To bond the articles together, a solvent is applied to the surface of the polymer article to attract radical initiators and monomers to the surface. Now, when the surface of the article comes into contact, the components in each article can react with the components in the other articles.

It is not necessary to apply the polymerizable monomer and radical initiator on the surface of both articles. For example, the polymerizable monomer may be applied to the surface of one article and the radical initiator may be applied to the surface of the other article. Alternatively, the polymerizable monomer and radical initiator may be applied only to the surface of one article. In another alternative, the radical formation initiator may be applied to the surface of one article and either the polymerizable monomer or the radical formation initiator may be applied to the surface of the other article.

A solvent can be used to attract the reactive component to the surface of the polymer article, but the polymer article can be contacted even before the initial solvent is completely removed.

The choice of polymerizable monomer and radical initiator can be the same as or different from that used for the formation of polymer articles. The polymer network of the article should have a density low enough to allow penetration by the polymerizable monomer in the radical initiator. For example, hydrogels can be useful in this regard.

B. Grafting a new polymer layer on the inside of the channel In another aspect, the wall of the channel can be coated with a material that has different properties than the material on which the channel wall is made. This can change the chemistry of the channel. Grafting can be performed, for example, by diffusion cross-linking methods. For example, the method may include applying a high molecular weight PEG to the lumen of the microfluidic channel to improve the biofouling prevention properties of the inner surface.

A thin film can be added inside the channel by flowing a solution containing a solvent, a radical initiator, and a polymerizable monomer (eg, high molecular weight PEG) through the channel, diffusing it into the lumen, and initiating the polymerization. A monomolecular layer can be formed by wetting the lumen with a monomer solution and grafting onto the lumen.

C. Methods of Joining Partially Hardened Polymers Partially hardened polymer articles can be joined together by placing the surfaces of the partially cured polymer together and initiating the polymerization again. The unpolymerized moieties on both polymer articles react with each other. In this way, the polymers of both articles are joined together into a single article.

D. Combining methods The methods described above for joining polymer layers together can be combined. For example, the first article may contain a fully cured polymer, while the second article may contain a partially cured polymer. The polymerizable monomer and radical initiator can be applied to the surface of a fully cured polymer. The surface of the article can then be brought into contact and polymerization can be initiated. In this case, the unreacted polymerizable moiety in the partially cured polymer is applied to the fully cured polymer so that the partially cured polymer is bonded to the fully cured polymer via the polymer network. Reacts with the polymerizable part.

V. Detaching individual devices from the master wafer In some embodiments, the mold and the first article produced from it have a pattern for each device with multiple microfeatures. Such an embodiment is shown in FIG. 14, for example. After molding the polymer articles and joining them together, the wafer-like pieces are separated into individual devices. Wafers can be separated by mechanical means such as sewing or by laser cutting.

VI. Device
A. Devices with Microfeatures The present disclosure provides polymer devices in which the polymer layer contains one or more microfeatures such as microchannels. Microchannels can extend the length of the polymer layer and open at the inlet and outlet at the ends of the layer. In some embodiments, the device comprises a solid lining bonded to one or both sides of the polymer layer along its width. In some embodiments, the polymer layer comprises two polymer layers bonded together. In such an embodiment, the microfeatures may be provided on the surface or in one or both layers prior to joining. Bonding can be achieved, for example, via an interpenetrating polymer network that interpenetrates both polymer layers. Alternatively, bonding can be achieved by bringing the two partially cured polymer layers into contact and completely curing. Both of these methods are described herein.

The devices of the present disclosure may be configured for use as medical devices, i.e., implantable in the human or animal body. In such cases, the device may include biocompatible materials. In certain embodiments, the polymer layer comprises a hydrogel.

In certain embodiments, the polymer layer contains a chemical or pharmaceutical product. Such compounds can be incorporated into the polymer at the polymerization stage, for example by diffusion bonding as described above. If the polymer is a hydrogel in which water in contact with the surface of the hydrogel, such as a microchannel, can diffuse in and out of the gel, then the chemical or pharmaceutical formulation can also diffuse from the polymer to the channel.

B. Microshunt The particular article provided in this disclosure is configured as a medical device. In particular, a particular device is configured as a microshunt in which the liquid is transported via one or more microchannels within the microfeature device. In such devices, the surface of the microchannel or the entire polymer layer on which the microfeatures are formed may contain a polymer having biofouling protection properties. Antibiofouling polymers prevent surface accumulation of microorganisms, plants, algae, proteins, and / or biomolecules on wet surfaces. PEG, zwitterionic polymers (containing positive and negative charges on the same chain, eg glycine, betaine, sulfobetaine methacrylate), poly (hydroxyfunctional acrylate), poly (2-oxazoline), poly (glycerol) , Poly (vinylpyrrolidone), peptides and several well-known polymers including peptoids exhibit this property.

If the device is intended to function as a permanent or temporary implant, the device is lined with a bioembedded material, i.e. a material that can be joined or fused with a biomaterial such as tissue. May include a layer of material. PET, thermoplastic polyurethane (“TPU”), and polyurethane are examples of such materials. The bioincorporated properties of the material can be improved by a local plasma etching process in which plasma is used to roughen the surface on a nanoscale and create more favorable surface chemistry for the cell. An array of plasma gases may be used for this purpose. This effect can be localized by physically masking the plasma with PDMS or a silicone membrane specially arranged with an array of pores. Such devices attach to the tissue at the fixation site and prevent cell adhesion near the edges that can block the inlet / exit.

Accordingly, microfluidic devices comprising first and second layers covalently bonded together and one or more microfluidic channels within the device are provided herein, wherein the first layer. The first and second layers contain the substrate and the polymer bonded to the substrate, respectively, and the two layers are bonded, for example, via a polymer network that interpenetrates the polymers in the first and second layers. There is. The microchannel may include, for example, one or more features selected from columns, weirs, and reservoirs. In some embodiments, the device comprises multiple intersecting microchannels. In another aspect, the plurality of channels do not intersect.

More specifically, the device is a channel in which the microchannel opens at the inlet and outlet in the polymer, at least one of the inlet and outlet is located at one or more ends, and the microchannel is located in the polymer. It can be configured as a microshunt, including an inlet and a channel outlet, the microshunt having a length of about 1 mm to about 10 mm and a width of about 0.1 mm to about 1 mm. In some embodiments, the device comprises a plurality of microfluidic channels, the channel having an inlet on the same side of the device and an exit on the same side of the device.

In some embodiments, the microshunt comprises a non-bioadhesive polymer sandwiched between solid substrates made of biointegrated materials, the polymer having a cut of 100 square microns to 10,000 square microns, eg, 1300 to 1600 square microns. It contains one or more microchannels having an area and having inlets and outlets that are open from the polymer, and the microshunts are about 0.5 mm to about 500 mm (eg, about 2 mm to about 5 mm) in length and about. It has an elongated shape with a width of 0.5 mm to about 10 mm (eg, a length of about 3 to 5 mm and a width of about 1 to 2 mm). A microshunt can include multiple microchannels.

The devices of the present disclosure may have a chip configuration. That is, they may have a generally flat configuration in which the thickness is substantially less than the length and / or width. For example, the length-to-thickness ratio can be at least 5: 1, at least 10: 1, or at least 20: 1. The width of the device is typically greater than or equal to the thickness. Typically, the top and bottom of the device will each be substantially planar and substantially parallel to each other. For example, the chip may have a substantially rectangular parallelepiped shape.

In certain embodiments, the chip comprises an aperture that extends to the width of the chip, i.e., passes through the chip through a substrate layer and a polymer layer. Therefore, the microshunts of the present disclosure may have a non-tubular shape.

VII. Methods of Use The microshunts of the present disclosure are useful as medical devices for transporting liquid fluids from areas of higher pressure to areas of lower pressure. Accordingly, the present disclosure provides a method comprising the following steps: (a) the shunt of the present disclosure to a body part containing a liquid, the inlet of the microchannel located in the cavity of the body part and the exit. The step of inserting so as to be located on the outside of the body part; and (b) the step of draining the liquid from the body part via the microfluidic channel. For example, a shunt can be an intraocular space, an intracranial space, a subcutaneous space, an intraperitoneal space, an intravesical space, a peritoneal cavity, the right atrium, a pleural space, a large cistern, an epicranial aponetic space, a paranasal sinus, the middle ear, or the kidney. Can be inserted into the inner space. The shunt can be inserted so that the entrance is located inside the body and the exit is located outside the body. Alternatively, both the entrance and exit of the shunt can be located inside the body.

Therefore, the present disclosure provides a method for treating glaucoma. The method comprises inserting the microshunt of the present disclosure into the intraocular space and draining the ocular fluid from the intraocular space to the outside of the body via one or more microchannels of the microshunt. The microshunt can be inserted at the edge of the iris. A corneal incision sword can be used to make an incision in the eye. The microshunt will be pushed slowly through the opening. If the microshunt contains a lining made of bioincorporated material, the shunt can be indwelled for extended periods of time. Glaucoma is characterized by an increase in pressure inside the eye, and because the environment outside the eye is atmospheric pressure, the fluid will flow from higher pressure to lower pressure, i.e. from the inside of the eye to the outside of the eye. Let's go.

The microchannels of the microshunt may have resistance to the flow of liquid so that the pressure inside the body part provides sufficient flow of liquid from the shunt inlet to the shunt outlet. For example, in a water drain device, multiple microchannels may have a fluid resistance of 1e13 to 2.3e14Pa * s / m ^ 3 (eg, 3.75e13Pa * s / m ^ 3). Dimensions to achieve such resistance can be achieved based on the algorithms provided herein.

The basic method for making the polymer device of the present disclosure is shown in FIG. Prepare two silanized PET substrates. Each of these is paired with a mold. In this example, one of the molds is a PVA-coated patterned silicone mold. The other mold is a non-patterned PDMS mold. The polymer is molded and bonded to the PET substrate. After molding, the device is laser processed into individual pieces. The device goes to the quality assurance inspection plan. They are then sterilized and packaged.

FIG. 2 shows an outline of the production of a silaneized substrate. Prepare the PET substrate. Hydroxy groups are generated on the PET substrate by exposure to plasma at 30 W for 60 minutes. The surface-reactive PET is contacted with silane in toluene in a polypropylene bag under a nitrogen atmosphere for 17 hours. After washing the functionalized substrate with alcohol and drying it in a vacuum oven at 120 ° for 2 hours, the silanized PET substrate is ready for use. FIG. 3 shows the chemistry of the coupling of (3-acryloxypropyl) trichlorosilane to the reactive PET surface.

Figure 4 shows the fabrication of a PVA-coated silicone mold. Silicone molds with multiple microfeature patterns are prepared and the microfeatures are prepared on the surface by etching. A solution of polyvinyl alcohol is prepared on the pattern surface of the substrate. Dry the substrate at 80 ° C. for 15 minutes in a vacuum oven. In this way, the mold is ready for use.

FIG. 5 shows the fabrication of a PDMS mold. Prepare a solution by mixing the PDMS substrate and the curing agent. The solution is sprayed onto the surface by rotating the spin coater at 2500 RPM for 60 seconds. The resulting polymer is dried in a vacuum oven at 120 ° C. for 10 minutes. The mold is molded by CO ₂ laser machining and is alcohol washed. In this way, the PDMS mold is ready for use.

FIG. 6 shows the start of photopolymerization. 2-Hydroxy-2-methylpropiophenone produces phenone radicals when exposed to light. The phenon radical couples with the acrylate group of triethylene glycol dimethacrylate.

FIG. 7 shows the polymerization of triethylene glycol dimethacrylate on surface-bonded acryloylsiloxane.

FIG. 8 shows the resulting crosslinked polymer of PEG bonded to the PET substrate.

FIG. 9 shows the fabrication of the microdevices of the present disclosure. Prepare a patterned mold and coat it with an anti-adhesion coating such as PVA. The polymer article is produced by coating the mold with a solution of the polymerizable monomer and a substrate having a polymerizable moiety and initiating the polymerization. The polymer article is removed from the mold and a photoinitiator and polymerizable monomer is applied to the surface of the polymer and diffused inward. A similar method is used to produce unpatterned polymeric articles. The polymer layers of both articles are brought into contact, in this case exposure to UV light initiates polymerization. Polymerization of polymerizable monomers creates a polymer network that spans both polymer articles and joins them together.

FIG. 10 shows a method for manufacturing a microfluidic device by partial hardening bonding. Prepare the mold. The mold is coated with a polymerizable monomer and a substrate. Start polymerization. However, the polymerization is stopped before the curing is complete, resulting in two partially cured polymer articles. The partially cured polymer of these two articles is brought into contact and polymerization is resumed. This causes the polymerizable monomers in both pieces to polymerize with each other. This joins the two pieces together.

FIG. 14 shows a template for making eight microfluidic devices. After production on a single piece, individual dies are cut from the master, for example by laser cutting or sewing.

FIG. 15 shows an exploded view of an exemplary water drainage device. The device includes an outer substrate layer of PET. The inner layer contains a PEG polymer. The layers are joined together by the methods described herein.

16A and 16B show exemplary emission devices of the present disclosure. The device contains an aperture shown as an open space. The open space gives the device a ring-like configuration. Open space promotes biointegration. The ejecting device is capable of lateral compression, allowing the device to pass through or enter an opening narrower than its uncompressed width. Therefore, this can achieve frictional fitting.

The design of the intraocular shunt can practice the aqueous humor dynamics model from the Alder's Physiology of the Eye 9th Edition recommended by the FDA. FIG. 17 shows a flowchart of this model. In determining the channel resistance, the parameters that affect the outflow must be specified. Possible parameters described in Alder's 10th Edition include: mean human supraccleral venous pressure (PE) = 9 mmHg, mean water influx = 2.5 μl / min, and grape scleral outflow in glaucoma ( U) = 0.3 μl / min. The trabecular meshwork outflow rate is calculated using Brubaker-Modification, which is responsible for the increased trabecular meshwork resistance at high IOPs. Individual trabecular meshwork outflow rates from healthy individuals to patients with severe glaucoma can be aggregated in volume R0.

FIG. 18 shows a dark area of intraocular pressure for glaucoma patients with varying levels of trabecular meshwork outflow. The R0 range is from 5.35, where the average inflow is 22 mmHg or higher, to 15, which is Alder's recommended maximum R0. Each figure shows the green area of the IOP value of the same patient with Model 8C BGI added. For reference, a blue line representing a healthy person is added (R0 = 3). Set a resistance that makes the pressure 10 mmHg with an inflow of 2.5 μl / min. Under these conditions, hypotension is unlikely even if the flow rate drops to 1.5 μl / min.

Abbreviation:
Fin --Total inflow
Fout-Total runoff
FS or S-Inflow from active secretions
FF-Inflow from filtration
FTrab-Traffic outflow
FU or U-Grape Sclera Outflow
FBGI --BGI outflow
PBlood-Mean arterial pressure
PE-Suprascleral venous pressure
IOP-Intraocular pressure
Cin- Inflow rate
CBGI --BGI outflow rate
CTrab-Traffic outflow rate
Ro --Bull Baker Resistance
Q --Bull Baker Closure Factor

IOP Dynamic Equilibrium Equation Assume that inflow is equal to outflow in steady state: Fin = Fout

Substituted inflow and outflow components: (FF + FS)-(FTrab + FU + FBGI) = 0

Detailed components:
Inflow from filtration: FF = (PBlood-IOP)
Inflow from secretion: FS = S
Uveoscleral outflow: FU = U = 0.3 μl / min (average of glaucoma patients from Alder's Physiology of the Eye, 10th Edition)
Trabecular meshwork outflow due to Bull Baker modification: FTrab = (IOP-PE) Ro + RoQ (IOP-PE) (from Alder's 9th and 10th Edition Q = 0.008, PE = 9mmHg). If the IOP is low, the runoff is close to the unmodified flow rate: FTrab ≒ (IOP-PE) * CTrab
BGI outflow: FBGI = IOP * CBGI

Complete Bull Baker Modification Equation: (PBlood-IOP) * Cin + S- (IOP-PE) Ro + RoQ (IOP-PE) -U-IOP * CBGI = 0

Simplified equation for channel determination: Fin = (IOP-PE) Ro + RoQ (IOP-PE) + U + IOP * CBGI

Assumption:
Steady state-Inflow equals outflow Average inflow is 2.5 μl / min (from Alder's 10th Edition)
U = 0.3 μl / min (from Alder's 10th Edition)
PE = 9mmHg (from Alder's 10th Edition)
Ro is 5.35 to 15 (resistance that results in IOP exceeding 22 mmHg with average inflow);
Q = 0.008 (from Alder's 9th Edition)

All publications and patent applications mentioned herein are incorporated herein by reference to the same extent that individual publications or patent applications are specifically and individually indicated to be incorporated by reference. ..

Although specific embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that such embodiments are provided merely by way of illustration. Those skilled in the art will come up with many modifications, changes, and replacements without departing from the invention. It should be understood that various alternatives to the aspects of the invention described herein may be employed in carrying out the invention. It is intended that the appended claims define the scope of the invention and that the methods and structures within these claims and their equivalents are included in the claims.

Claims (15)

(a) A step of preparing a first polymer article having a polymer layer having a first surface and a second polymer article having a polymer layer having a second surface ;
(b) Step of contacting the first surface with the radical formation initiator and the components of the polymerizable monomer;
(c) The step of bringing the second surface of the second polymer article into contact with the first surface of the first polymer article ;
(d) A step of initiating polymerization to produce a graft polymer of a monomer, which comprises grafting a first polymer article to a second polymer article.
A method of grafting two polymer articles together, wherein the polymer layer contains hydrogel . The method of claim 1, wherein the polymer layer has biofouling-preventing properties. 13. Method. The method of claim 1, wherein at least one polymer layer comprises one or more microfeatures. The method of claim 4 , wherein at least one microfeature is a microchannel. The method of claim 1, wherein the polymerizable monomer reacts with polyethylene glycol having a polymerizable group (“PEG”). The method of claim 6 , wherein the polyethylene glycol having a polymerizable group comprises triethylene glycol dimethacrylate. The method of claim 1 , wherein the first polymer article and / or the second polymer article comprises a polymer layer covalently bonded to a substrate. The first polymer article and the second polymer article are prepared by a method comprising the step of preparing a solid substrate, which is contained in the polymer article and includes a surface containing a polymerizable moiety, and the solid substrate is polyethylene terephthalate (“PET”). , Poly (methyl methacrylate) ("PMMA"), Polyurethane ("PU"), Polycarbonate ("PC"), Polyvinyl chloride ("PVC"), Polypoly alcohol ("PVA"), Polystyrene ("PS"), Thermoplastic polyurethane (“TPU”), polyethylene (“PE”), polysulfone, polyethersulfone (“PES”), sulfonated polyethersulfone (“SPES”), polybutylene terephthalate (“PBT”), polyhydroxyalkano Ate (“PHA”), silicone, parylene, polypropylene (“PP”), fluoropolymer, polyhydroxylethyl methacrylate (“pHEMA”), polyetherketoneketone (“PEKK”), polyetheretherketone (“PEEK”) , Polyetheretherketone ("PAEK"), Lactic acid-glycolic acid copolymer ("PLGA"), Polytetrafluoroethylene ("PTFE"), Polyfluorinated vinylidene ("PVDF"), and Polyacrylic acid ("PAA") The method of claim 1 , comprising a more selected substance. The first polymer article and the second polymer article are prepared by a method including a step of preparing a solid substrate, which is contained in the polymer article and includes a surface containing a polymerizable moiety, and a step of preparing the solid substrate is a step of preparing the polymer substrate. The method of claim 1 , comprising a step of functionalizing with a hydroxyl group and a step of coupling (3-acryloxypropyl) trichlorosilane via the hydroxyl group. The first polymer article and the second polymer article are prepared by a method comprising the step of preparing a solid substrate, which is contained in the polymer article and includes a surface containing a polymerizable moiety, and further physical the surface for surface hydroxyl activation. The method of claim 1 , comprising the step of sensitizing to a physical or chemical treatment. The steps of preparing the first polymer article and the second polymer article are the steps of preparing a mold having one or more microfeatures optionally, and the step of superimposing the components of the polymerizable monomer and the radical formation initiator on the mold. The method according to claim 1 , further comprising a step of optionally aligning the mold with the solid substrate, a step of initiating polymerization , and a step of removing the mold . 12. The method of claim 12 , wherein the mold comprises silicon coated with polyvinyl alcohol (“PVA”), polydimethylsiloxane (“PDMS”), SU-8 epoxy, parylene, PTFE, dry film photoresist, or glass. .. 12. The method of claim 12 , wherein the mold comprises a plurality of microfeature patterns, each pattern corresponding to one of a plurality of microdevices. For at least one article, the polymerizable monomer and radical initiator components further contact the mold, which imparts microchannels to the polymer, whereby the final device comprises closed microchannels, claim 1 . The method described.

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